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Benhammou et al. Hepatoma Res 2020;6:35 I http://dx.doi.org/10.20517/2394-5079.2020.16 Page 9 of 15

Figure 1. Schematic diagram of the spectrum of NAFLD to NAFLD-associated HCC and the clinical factors implicated in its pathogenesis
or prevention. NAFLD: nonalcoholic fatty liver disease; HCC: hepatocellular carcinoma; ASA: aspirin

resection instead of liver transplantation [121] .

Interestingly, statin use or dyslipidemia also appears to have different effects on non-cirrhosis HCC patients.
For instance, using Taiwan’s National Health Insurance Research Database that included 31,751 NAFLD
[13]
patients from 1998-2012, Lee et al. demonstrated that patients on statin therapy (35% of all patients) had a
decreased risk for HCC (adjusted HR = 0.29, 95%CI: 0.21-0.68). Few other studies have addressed the effects
of statins between the cirrhosis and non-cirrhosis NAFLD patient, which necessitates future work in this
area.

Animal studies have shed some light on the pathogenesis of NAFLD and NAFLD-associated HCC.
Through a series of detailed experiments, Grohmann et al. [122] demonstrate that while obesity promotes
NASH pathogenesis through STAT-1 (signal transducer and activator of transcription 1) activation, NASH-
associated HCC is mostly driven by STAT-3 (signal transducer and activator of transcription 3), a transcription
factor implicated in the immune system. They further corroborated this using human samples as proof
of concept. Their work was complimentary to previous reports showing that STAT-3 activation correlates
with tumor aggressiveness and prognosis [123,124] . As our knowledge of NAFLD and NAFLD-associated HCC
advances, it is becoming evident that the two diseases are divergent and should, potentially, be thought of
as separate entities and not on the same spectrum [Figure 1]. This is also apparent in our epidemiological
studies where we found that NAFLD-associated HCC tended to occur in non-Hispanic patients, suggesting
different mechanisms of action between the cirrhosis and non-cirrhosis patient populations (manuscript
submitted).

SCREENING?
Expert societies recommend HCC screening with bi-annual ultrasounds with or without alpha-fetal protein
(AFP) or other biomarkers, based on its cost-effectiveness and benefits [125,126] . Although the incidence of
NAFLD-associated HCC remains low overall, given the magnitude of MetS and the NAFLD epidemic,
NAFLD-HCC cases are expected to increase. Since HCC can also occur in a non-cirrhotic background,
future research is imperative in this field to identify at-risk patient populations that would benefit from
screening programs, which have largely operated under a “one-size-fits-all” model. Unlike hepatitis C, B and